Englander Institute for Precision Medicine

Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition.

TitleKinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition.
Publication TypeJournal Article
Year of Publication2025
AuthorsRowdo FPMadorsky, Martini R, Ackermann SE, Tang CP, Tranquille M, Irizarry A, Us I, Alawa O, Moyer JE, Sigouros M, Nguyen J, Assaad MAl, Cheng E, Ginter PS, Manohar J, Stonaker B, Boateng R, Oppong JK, Adjei EK, Awuah B, Kyei I, Aitpillah FS, Adinku MO, Ankomah K, Osei-Bonsu EB, Gyan KK, Hoda S, Newman L, Mosquera JMiguel, Sboner A, Elemento O, Dow LE, Davis MB, M Martin L
JournalCancer Res
Volume85
Issue3
Pagination551-566
Date Published2025 Feb 01
ISSN1538-7445
KeywordsBlack People, Breast Neoplasms, CRISPR-Cas Systems, ErbB Receptors, Female, Humans, Organoids, Protein Kinase Inhibitors, Receptor, Fibroblast Growth Factor, Type 1
Abstract

Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407.

DOI10.1158/0008-5472.CAN-24-0775
Alternate JournalCancer Res
PubMed ID39891928
Grant List / / Weill Cornell Medicine (WCM) /
BCRF-22-191 / / Breast Cancer Research Foundation (BCRF) /
CA259396-01 / / National Cancer Institute (NCI) /

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